The activity of rat brain tryptophan hydroxylase (TH) is increased 2-fold by heparin and 4-fold by dextran sulfate. Hyaluronic acid, chondroitin sulfate, and dermatan sulfate as well as the unsulfated polymer dextran do not alter hydroxylase activity. Heparin and dextran sulfate decrease the apparent Km of the enzyme for both substrates 5MPH4 and tryptophan as well as increasing the -Vmax. A variety of polyanions (DNA, glycogen, poly-d-and poly-e-glutamic acid) have no effect on TH whereas salts (NaCl, KCl, (NH4)2 SO4 and MgSO4) inhibit the enzyme, indicating that the effects of heparin and dextran sulfate on TH are not mediated by increases in ionic strength per se. Several lines of data suggest that TH binds ionically to these polyelectrolytes: (1) The activation produced by heparin and dextran sulfate diminishes as the ionic strength of the assay medium increases, (2) TH binds to heparin substituted Sepharose 4B and is eluted by increasing the ionic strength of the eluant buffer, and (3) large molecular weight dextran sulfate (MW=500,000) dramatically shifts the elution profile of TH from a Kav of 0.41 to a Kav of 0.10 on a Sepharose/CL-6B column. These data suggest that binding of certain poly-electrolytes to TH induces a conformational change in the enzyme resulting in increased catalytic activity.